key: cord-336563-hwemigk7
authors: Bhimraj, Adarsh; Morgan, Rebecca L; Shumaker, Amy Hirsch; Lavergne, Valery; Baden, Lindsey; Cheng, Vincent Chi-Chung; Edwards, Kathryn M; Gandhi, Rajesh; Muller, William J; O’Horo, John C; Shoham, Shmuel; Murad, M Hassan; Mustafa, Reem A; Sultan, Shahnaz; Falck-Ytter, Yngve
title: Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19
date: 2020-04-27
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa478
sha: 
doc_id: 336563
cord_uid: hwemigk7

BACKGROUND: There are many pharmacologic therapies that are being used or considered for treatment of COVID-19. There is a need for frequently updated practice guidelines on their use, based on critical evaluation of rapidly emerging literature. OBJECTIVE: Develop evidence-based rapid guidelines intended to support patients, clinicians and other health-care professionals in their decisions about treatment and management of patients with COVID-19. METHODS: IDSA formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise. Process followed a rapid recommendation checklist. The panel prioritized questions and outcomes. Then a systematic review of the peer-reviewed and grey literature was conducted. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations. RESULTS: The IDSA guideline panel agreed on 7 treatment recommendations and provided narrative summaries of other treatments undergoing evaluations. CONCLUSIONS: The panel expressed the overarching goal that patients be recruited into ongoing trials, which would provide much needed evidence on the efficacy and safety of various therapies for COVID-19, given that we could not make a determination whether the benefits outweigh harms for most treatments.

A c c e p t e d M a n u s c r i p t

It is important to realize that guidelines cannot always account for individual variation among patients. They are assessments of current scientific and clinical information provided as an educational service; are not continually updated and may not reflect the most recent evidence (new evidence may emerge between the time information is developed and when it is published or read); should not be considered inclusive of all proper treatments methods of care, or as a statement of the standard of care; do not mandate any particular course of medical care; and are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Whether and the extent to which to follow guidelines is voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. While IDSA makes every effort to present accurate, complete, and reliable information, these guidelines are presented "as is" without any warranty, either express or implied. IDSA (and its officers, directors, members, employees, and agents) assume no responsibility for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential damages, incurred in connection with these guidelines or reliance on the information presented.

The guidelines represent the proprietary and copyrighted property of IDSA. Copyright 2020 Infectious Diseases Society of America. All rights reserved. No part of these guidelines may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of IDSA. Permission is granted to physicians and health care providers solely to copy and use the guidelines in their professional practices and clinical decision-making. No license or permission is granted to any person or entity, and prior written authorization by IDSA is required, to sell, distribute, or modify the guidelines, or to make derivative works of or incorporate the guidelines into any product, including but not limited to clinical decision support software or any other software product. Except for the permission granted above, any person or entity desiring to use the guidelines in any way must contact IDSA for approval in accordance with the terms and conditions of third-party use, in particular any use of the guidelines in any software product.

Executive Summary COVID-19 is a pandemic with a rapidly increasing incidence of infections and deaths. Many pharmacologic therapies are being used or considered for treatment. Given the rapidity of emerging literature, IDSA identified the need to develop living, frequently updated evidence-based guidelines to support patients, clinicians and other health-care professionals in their decisions about treatment and management of patients with COVID-19.

Summarized below are the recommendations with comments related to the clinical practice guideline for the treatment and management of COVID-19. A detailed description of background, methods, evidence summary and rationale that support each recommendation, and research needs can be found online in the full text. In brief, per GRADE methodology, recommendations are labeled M a n u s c r i p t as "strong" or "conditional". The word "recommend" indicates strong recommendations and "suggest" indicates conditional recommendations. In situations where promising interventions were judged to have insufficient evidence of benefit to support their use and with potential appreciable harms or costs, the expert panel recommended their use in the context of a clinical trial. The guideline panel used the word "only" in recommendations about therapeutic agents with higher uncertainty and/or more potential for harm. These recommendations acknowledge the current "knowledge gap" and aim at avoiding premature favorable recommendations for potentially ineffective or harmful interventions. The panel expressed the overarching goal that patients be recruited into ongoing trials, which would provide much needed evidence on the efficacy and safety of various therapies for COVID-19. The panel determined that when an explicit trade-off between the highly uncertain benefits and the known putative harms of these therapeutic agents were considered, a net positive benefit was not reached and could possibly be negative (risk of excess harm). The panel acknowledges that enrolling patients in RCTs might not be feasible for many frontline providers due to limited access and infrastructure. Should lack of access to clinical trials exist, we encourage setting up local or collaborative registries to systematically evaluate the efficacy and safety of drugs to contribute to the knowledge base. Each clinician can play a role in advancing our understanding of this disease through a local registry or other data collection efforts. M a n u s c r i p t Background The first cases of coronavirus disease 2019 (COVID-19) were reported from Wuhan, China in early December 2019 [1] , now known to be caused by a novel beta-coronavirus, named as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a span of months COVID 19 has become pandemic due to its transmissibility, spreading across continents with the number of cases and deaths rising daily [2] . Although most infected individuals exhibit a mild illness (80%+), 14% have serious and 5% have critical illness. Approximately 10% will require hospital admission due to COVID-19 pneumonia, of which approximately 10% will require ICU care, including invasive ventilation due to acute respiratory distress syndrome (ARDS) [3] . While mortality appears to be more common in older individuals and those with comorbidities, such as chronic lung disease, cardiovascular disease, hypertension and diabetes, young people with no comorbidities also appear to be at risk for critical illness including multi-organ failure and death.

There has been an expanding number of studies rapidly published online and in academic journals; however, some of these may be of limited quality and are pre-published without sufficient peerreview. Critical appraisal of the existing studies is needed to determine if the existing evidence is sufficient to support currently proposed management strategies.

Given the rapid global spread of SARS CoV-2 and the difficulty for the overburdened front-line providers and policymakers to stay up to date on emerging literature, IDSA has recognized the necessity of developing a rapid guideline for the treatment of COVID-19. The guideline panel used a methodologically rigorous process for evaluating the best available evidence and providing treatment recommendations. Two additional guidelines on diagnostic testing and infection prevention are also under development. These guidelines will be frequently updated as substantive literature becomes available and will be accessible on an easy to navigate web and device interface at http://www.idsociety.org/covid19guidelines. The guideline panel considered making a recommendation for therapeutic agents that were currently available for use. The panel chose not to give a recommendation for remdesivir as it is mostly available in the context of ongoing trials with limited availability for compassionate use and expanded access use. We anticipate data from RCTs for remdesivir will be soon available; at that point, we will update the guidelines to provide formal recommendations on its use.

There are several ongoing trials evaluating therapeutic agents for the treatment of COVID-19. As data becomes available from these trials and if there is a preponderance of evidence to suggest the use of a therapeutic agent even in the context of clinical trials is no longer warranted it will be removed from future updates of the guideline (and the removal will be noted in the updated A c c e p t e d M a n u s c r i p t guidelines). If there is emerging evidence on the efficacy or safety of a therapeutic agent not mentioned in the current version of the guideline it will be included in future updates of the guideline.

These recommendations are intended to inform patients, clinicians, and other health professionals by providing the latest available evidence.

This guideline was developed using the GRADE approach for evidence assessment. In addition, given the need for an urgent response to a major public health crisis, the methodological approach was modified according to the GIN/McMaster checklist for the development of rapid recommendations [4] .

The panel was composed of nine members including front line clinicians, infectious diseases specialists who are members of the IDSA, the HIV Medical Association (HIVMA), the Society for Healthcare Epidemiology of America (SHEA), and the Pediatric Infectious Diseases Society (PIDS). They represented the disciplines of public health, pharmacology, pediatrics, medical microbiology, preventive care, critical care, as well as hepatology, nephrology and gastroenterology. The Evidence Foundation provided technical support and guideline methodologists for the development of this guideline.

The conflict of interest (COI) review group included two representatives from IDSA who were responsible for reviewing, evaluating and approving all disclosures. All members of the expert panel complied with the COI process for reviewing and managing conflicts of interest, which required disclosure of any financial, intellectual, or other interest that might be construed as constituting an actual, potential, or apparent conflict, regardless of relevancy to the guideline topic. The assessment of disclosed relationships for possible COI was based on the relative weight of the financial relationship (i.e., monetary amount) and the relevance of the relationship (i.e., the degree to which an association might reasonably be interpreted by an independent observer as related to the topic or recommendation of consideration). The COI review group ensured that the majority of the panel and chair was without potential relevant (related to the topic) conflicts. The chair and all members of the technical team were determined to be unconflicted. M a n u s c r i p t

Clinical questions were developed into a PICO format (Population, Intervention, Comparison, Outcomes) [5] prior to the first panel meeting. Panel members prioritized questions with available evidence that met the minimum acceptable criteria (i.e., the body of evidence reported on at least a case-series design, case reports were excluded). Panel members prioritized patient-important outcomes such as mortality, development of ARDS (need for non-invasive or invasive ventilation) and clinical improvement (such as disease-oriented outcomes inferred by radiological findings or virologic cure), and severe adverse events leading to treatment discontinuation. Additional drug specific harms were evaluated when clinically relevant, including possible drug-drug reactions, if applicable.

The NICE highly-sensitive search was reviewed by the methodologist in consultation with the technical team information specialist and was determined to have high sensitivity [6] . An additional term, COVID, was added to the search strategy used in addition to the treatment terms identified in the PICO questions (Supplementary Table s1 ). Ovid Medline and Embase were searched from 2019 through April 4, 2020. Horizon scans were performed daily during the evidence assessment and recommendation process to locate additional grey literature and manuscript pre-prints. Reference lists and literature suggested by panelists were reviewed for inclusion. No restrictions were placed on language or study type.

Two reviewers independently screened titles and abstracts, as well as eligible full-text studies. When acceptable randomized controlled trials of effectiveness were found, no additional non-randomized studies or non-comparative evidence (i.e., single arm case series) were sought. Evidence from single arm studies reporting on non-comparative rates of outcomes of interest were included if a historical control event rate could be estimated from the literature. Reviewers extracted relevant information into a standardized data extraction form.

For several interventions, no direct evidence was available other than case reports or mechanistic considerations. The panel either decided to include plausible indirect evidence and make a recommendation (e.g., from studies of SARS-CoV) or to provide a short narrative discussion of the intervention.

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Data extracted from the available evidence included: mortality, clinical progression or improvement as reported in the studies, virologic clearance, and adverse events. Where applicable, data were pooled using random effects model (fixed effects model for 2 or less trials or pooling of rates) using RevMan or OpenMeta [7] .

Cochrane risk of bias tools for randomized clinical trials (RCTs) and Observational Studies and modified domains were used in assessing confounding bias, selection bias, and misclassification bias [8] . The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [9] . Within GRADE, the body of evidence across each outcome is assessed for domains that may reduce or increase one's certainty in the evidence. Factors that may reduce one's certainty include risk of bias (study limitations), inconsistency (unexplained heterogeneity across study findings), indirectness (applicability or generalizability to the research question), imprecision (the confidence in the estimate of an effect to support a particular decision) or publication bias (selective publication of studies). One's certainty in the evidence may be strengthened if the following considerations are present: large or very large magnitude of effect, evidence of a dose-response gradient, or opposing residual confounding. GRADE summary of findings tables were developed in GRADEpro Guideline Development Tool [10] .

The panel considered core elements of the GRADE evidence in the decision process, including Certainty of evidence and balance between desirable and undesirable effects. Additional domains were acknowledged where applicable (feasibility, resource use, acceptability). For all recommendations, the expert panelists reached consensus. Voting rules were agreed on prior to the panel meetings for situations when consensus could not be reached.

As per GRADE methodology, recommendations are labeled as "strong" or "conditional". The words "we recommend" indicate strong recommendations and "we suggest" indicate conditional recommendations. Figure 1 provides the suggested interpretation of strong and weak recommendations for patients, clinicians, and healthcare policymakers. For recommendations where the comparators are not formally stated, the comparison of interest is implicitly referred to as "not using the intervention". The guideline panel used the word "only" in recommendations about therapeutic agents with higher uncertainty and/or more potential for harm. For example, the toxicity of hydroxychloroquine/chloroquine plus azithromycin (Recommendation 2) carries particular risk for patients in the outpatient setting who may not be enrolled in a trial and therefore may have inadequate monitoring; or, for Recommendation 6, there is concern related to tocilizumab shortages for other indications and potential toxicity of worsening infection/drug interactions. These recommendations acknowledge the current "knowledge gap" and aim at avoiding premature favorable recommendations for their use and to avoid encouraging the rapid M a n u s c r i p t diffusion of potentially ineffective or harmful interventions. Detailed suggestions about the specific research questions that should be addressed are found in the table (see Supplementary Table s2 ). M a n u s c r i p t

Regular, frequent screening of the literature will take place to determine the need for revisions based on the likelihood that any new data will have an impact on the recommendations. If necessary, the entire expert panel will be reconvened to discuss potential changes. 

Two RCTs of patients with confirmed COVID-19 with mild pneumonia (e.g., positive CT scan without oxygen requirement) or non-severe infection admitted to the hospital treated with hydroxychloroquine (HCQ) reported on mortality at 14 days, clinical progression (radiological progression on CT scan), clinical improvement, failure of virologic clearance (PCR), and adverse events (both) [11, 12] (Table 1 ).

In addition, we identified four publications describing three trials of combination treatment with HCQ plus azithromycin (AZ) among hospitalized patients with COVID-19 reporting on the outcomes of mortality, failure of virologic clearance (assessed with PCR test), and adverse events (i.e., significant QT prolongation leading to treatment discontinuation) [13] [14] [15] [16] (Table 2) .

The currently available best evidence failed to demonstrate or to exclude a beneficial effect of HCQ on clinical progression of COVID-19 (as inferred by radiological findings; RR: 0.61; 95% CI: 0.26, 1.43; see Figure s2 ), or on viral clearance by PCR tests (RR: 2.00; 95% CI: 0.02, 20.00; see Figure s3 ), although a somewhat higher proportion in the HCQ group experienced clinical improvement (RR: 1.47; 95% CI 1.02, 2.11). However, the certainty in the evidence was rated as very low mainly due to small sample sizes (sparse data), co-interventions, and risk of bias due to methodological limitations. In addition, the selected outcomes should be considered indirect, as important patient outcomes (e.g., mortality, rate of progression to ARDS and need for mechanical ventilation) were unavailable.

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Studies evaluating the addition of azithromycin to HCQ provided indirect comparisons of failure of virologic clearance to historical controls. The observed risk of mortality among patients receiving HCQ+AZ during hospital stay was 3.4% (6/175 patients). However, an estimated mortality rate in an untreated cohort was not provided in the manuscript. When compared to a lack of viral clearance in historical controls (100% virologic failure), 12 symptomatic patients were compared at day 5 or 6 from a separate hospital in France. Patients receiving treatment with HCQ+AZ experienced numerically fewer cases of virologic failure (43% pooled virologic failure; 29/71 patients) (Figure s3 ). There is very low certainty in this comparison of treatment effect mainly due to very high-risk selection bias, making any claims of effectiveness highly uncertain. In addition, relying on intermediary outcomes, such as viral clearance to determine patient-important outcomes (including a reduction in development of pneumonia, hospital or ICU admission, or need for intubation) add another layer of imprecision.

Two studies described significant QT prolongation in 10 of 95 treated patients, either resulting in an QT increase to over 500 ms or discontinuation of the HCQ/AZ treatment, illustrating the high risk for clinically relevant arrhythmias for this treatment [15, 16] . In addition, several case reports of QT prolongation related to hydroxychloroquine have also been published [17] [18] [19] [20] .

In another prospective cohort study in 224 COVID-19 uninfected patients with SLE who received either chloroquine or hydroxychloroquine for routine care, gastrointestinal side effects occurred in 7% of patients [21] .

Several case reports have been published citing the risk of a prolonged QT prolongation, torsades de pointes, and ventricular tachycardia in patients receiving azithromycin alone. In a large cohort study, patients taking a five-day course of azithromycin had an increased risk of sudden cardiac death with a hazard ratio of 2.71 (1.58-4.64) vs. 0.85 (0.45-1.60), compared to patients receiving no antibiotic or amoxicillin, respectively [22] . Given the cumulative effect on cardiac conduction seen with hydroxychloroquine and azithromycin, if this combination was to be used in the context of a clinical trial, baseline and follow-up ECG monitoring would be indicated, as well as careful surveillance for other concomitant medications known to prolong the QT interval.

Renal clearance accounts for 15-25% of total clearance of hydroxychloroquine, however dose adjustments are not recommended according to package labeling. Chloroquine and hydroxychloroquine are metabolized by cytochrome P450 isoenzymes 2C8, 2D6, and 3A4 [23] , therefore inhibitors and inducers of these enzymes may result in altered pharmacokinetics of these agents.

Providers are encouraged to visit resources such as the newly created website, https://www.covid19-druginteractions.org/ to aid in the evaluation and management of drug interactions with current and emerging investigational agents for COVID-19.

Azithromycin is low risk for cytochrome P450 interactions [24] ; however additional pharmacologic adverse events including gastrointestinal effects and QT prolongation need to be carefully considered particularly in the outpatient setting where frequent ECG monitoring is not feasible.

A c c e p t e d M a n u s c r i p t

The panel agreed that the overall certainty of evidence was very low due to concerns with risk of bias, inconsistency, indirectness, imprecision, and publication bias.

The guideline panel recommends that, because of uncertainty regarding its risks and benefits, the use of HCQ should be in the context of a clinical trial. Because of the potential for toxicity, the panel recommends that the HCQ+AZ combination only be used in the context of a clinical trial. This recommendation does not address the use of azithromycin for secondary bacterial pneumonia in patients with COVID-19. Additional randomized controlled trials and prospective outcome registries are needed to inform research for treatment with HCQ alone or in combination with azithromycin for patients with COVID-19 (Table s2 . Best practices/suggestions for research of treatments for patients with COVID-19).

One RCT and two case studies reported on treatment with combination lopinavir/ritonavir for hospitalized patients with COVID-19 [25] [26] [27] (Table 3) . Cao et al. randomized 199 hospitalized patients with severe COVID-19 to receive treatment with lopinavir/ritonavir in addition to standard of care (n=99) or standard of care alone (n=100) for 14 days. The trial reported on the following outcomes: mortality, failure of clinical improvement (measured using a 7-point scale or hospital discharge), and adverse events leading to treatment discontinuation.

Based on a modified intention to treat analysis, treatment with lopinavir/ritonavir failed to show or exclude a beneficial effect on mortality (RR: 0.67; 95% CI: 0.38, 1.17), although failure of clinical improvement was lower in the lopinavir group (RR: 0.78; 95% CI: 0.63, 0.97; ITT analysis).

Nearly 14% of lopinavir/ritonavir recipients were unable to complete the full 14-day course of administration due primarily to gastrointestinal adverse events, including anorexia, nausea, abdominal discomfort, or diarrhea, as well as two serious adverse episodes of acute gastritis. Two recipients also had self-limited skin eruptions. The risk of hepatic injury, pancreatitis, severe cutaneous eruptions, QT prolongation, and the potential for multiple drug interactions due to CYP3A inhibition, are all well documented with this drug combination.

The panel elected to inform their decision based on the RCT [27] . The panel determined the Certainty of evidence to be very low due to concerns with risk of bias (lack of blinding) and imprecision. In the randomized clinical trial conducted by Cao et al, the group that received lopinavir/ritonavir and the group that did not had similar rates of viral decay. This finding suggests that lopinavir/ritonavir is not having a measurable antiviral effect, its purported mechanism of action.

The guideline panel recommends the use of lopinavir/ritonavir only in the context of a clinical trial. Additional clinical trials or prospective outcome registries are needed to inform research for treatment with lopinavir/ritonavir and other HIV-1 protease inhibitors for patients with COVID-19 (Supplementary Table s2) . 

The panel determined that due to the limitation of direct COVID-19 data, indirect evidence from the 2003 SARS outbreak and from MERS would also be considered. A systematic review [30] reported on 15 studies, 13 of which were inconclusive to any benefits of corticosteroids. One RCT reported that SARS-CoV-1 viral loads showed delayed viral clearance associated with corticosteroid use.

The same review also reported on a subset of ARDS patients (three trials). One small RCT in 24 patients using a lower dose methylprednisolone for two days showed possible improvement of ARDS; however, two larger trials showed little or no effect in critically ill patients with pulmonary failure. The authors concluded that despite widespread use of corticosteroids during the SARS outbreak, conclusive evidence of benefit was lacking and that administering steroids early in the disease process before viral replication is controlled may lead to a delay in viral clearance.

The panel deemed the certainty of the direct evidence as very low owing to concerns with risk of bias, inconsistency, and imprecision. The panel based their decision to conditionally recommend against the use of corticosteroids among patients admitted to the hospital on the indirect findings from the systematic review on SARS-CoV.

M a n u s c r i p t

As COVID-19is a self-limited viral illness in most cases, a small subset of patients progresses from COVID-19 pneumonia to develop ARDS. Based on limited data from other coronaviruses, there is no clear benefit and potential harm from corticosteroids. Carefully designed RCTs and prospective outcome registries are needed to determine the dose, route, timing, and duration of such treatment on the prevention of clinical deterioration and to better understand the potential harms associated with its use. If a person is on a steroid (inhaled or systemic) for another indication (e.g., asthma), the steroid should be continued.

M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t

Studies reporting on the pathogenesis of SARS and MERS-CoV suggest a release of proinflammatory cytokines including interleukins-6 (IL-6) [31] during the clinical illness. Our search identified one study [31] that reported on 21 severe or critical patients with COVID-19 treated with tocilizumab, an IL-6 blocker ( Table 6 ). This study had no control group. To estimate a control group rate in patients who did not get treatment with tocilizumab, Xu et al. described findings from Yang 2020, which suggested a baseline mortality rate of 60% in critical patients and 11% in severe patients admitted to the ICU [32] .

We estimate that the patients in Xu 2020 (21 patients, 4 critical and 17 severe) would have a baseline mortality risk of 20% as matched in severity. Therefore, treatment with tocilizumab may have reduced mortality since there were no deaths reported out of 21 patients. However, this conclusion remains highly uncertain given the lack of a contemporaneous control or adjustments for confounding factors. Out of 21 patients, 19 were discharged from the hospital suggesting a 9.5% rate of failure of clinical improvement in the CT scan findings.

Xu et al. reported no serious adverse events [31] . However, patients receiving tocilizumab are often at an increased risk of serious infections (bacterial, viral, invasive fungal infections, and tuberculosis) and hepatitis B reactivation [33] . Cases of anaphylaxis, severe allergic reactions, severe liver damage and hepatic failure, and intestinal perforation have been reported after tocilizumab administration in patients without COVID-19.

Tocilizumab is not metabolized by the cytochrome P450 isoenzyme system, however elevated IL-6 levels seen in inflammatory states have been shown to inhibit these enzymes, thereby slowing the metabolism of drugs through these pathways. As the 3A4 pathway is responsible for metabolism of many commonly used medications, administration of IL-6 inhibitors like tocilizumab may result in enhanced metabolism in drugs utilizing the cytochrome P450 system [34, 35] .

The panel determined that the overall certainty of the evidence was very low due to concerns of high risk of bias due to confounding, indirectness, and imprecision.

M a n u s c r i p t

The guideline panel recommended tocilizumab only in the context of a clinical trial. Additional clinical trials are needed to inform research on the effectiveness of treatment with tocilizumab for patients with COVID-19 (Supplementary Table s2 ).

M a n u s c r i p t A c c e p t e d M a n u s c r i p t

Our search identified two case series of a total of 15 patients reporting on the outcomes of mortality, failure of clinical improvement (as inferred by need for continued mechanical ventilation), and treatment related adverse events among hospitalized patients with COVID-19 (Table 7 ) [36, 37] . All five patients in Shen 2020 were mechanically ventilated at time of treatment compared with three out of 10 patients in the Duan et al study.

Duan 2020 included a comparison of the 10 treated patients to 10 historical control patients matched on age, gender, and severity of illness. Both studies lacked adjustments for critical confounders including co-treatments, baseline characteristics, disease severity, and timing of plasma delivery.

Compared with a 30% mortality rate in the historical control (3/10), no deaths were reported among patients receiving COVID-19 convalescent plasma. Out of eight patients across both studies on mechanical ventilation at time of treatment, 50% (n=4) were extubated at time of data collection.

Among 10 patients, no serious adverse reactions or safety events were recorded following COVID-19 convalescent transfusion.

The panel agreed on the overall certainty of evidence as very low due to concerns with risk of bias and imprecision. Continuation of mechanical ventilation was used as a surrogate for failure of clinical improvement; however, the panel recognized the importance of the timeframe for extubation when associating it to plasma transfusion. Given the limited information provided about time of extubation, the panel recognized an additional knowledge gap with the assessment of this outcome.

The guideline panel recommends COVID-19 convalescent plasma in the context of a clinical trial. Additional clinical trials are needed to inform research for treatment with COVID-19 convalescent plasma for patients with COVID-19 (Supplementary Table s2 ).

M a n u s c r i p t

In addition to the clinical questions addressed above, the panel identified several treatments currently undergoing evaluation for which additional data are needed to formulate recommendations. Narrative summaries for these treatments are provided below.

In-vitro antiviral activity of darunavir against SARS-CoV-2 showed no activity at clinically relevant concentrations.

Three randomized, open-label clinical trials are currently listed on clinicaltrials.gov evaluating darunavir/cobicistat as a potential therapeutic option for COVID-19. Janssen, the manufacturer of darunavir/cobcistat has reported that one of these trials [38] has concluded that darunavir/cobicstat plus conventional treatments was not effective in achieving viral clearance at day seven post randomization, M a n u s c r i p t compared to conventional treatments alone. Clinical outcomes of this trial including rate of critical illness and mortality 14 days after randomization, have not been reported to date.

Lopinavir-ritonavir is a combination of protease inhibitors for the treatment of HIV infection. Lopinavir-ritonavir has been shown to have in-vitro antiviral activity against beta-coronaviruses such as SARS-CoV, and MERS-CoV [39] [40] [41] [42] . Since lopinavir-ritonavir is not specifically designed for treatment of coronavirus, lopinavir-ritonavir alone may not demonstrate a difference from placebo in reducing viral load when treatment was initiated at a median of 13 days after symptoms onset [41] . In an open label treatment trial, lopinavir-ritonavir with ribavirin reduced the mortality and requirement of intensive care support of hospitalized SARS patients compared with historical control [41] . Many interferons, especially interferon beta have been shown to have modest in-vitro antiviral activity against SARS-CoV and MERS-CoV [39, 40] . Lopinavir-ritonavir or interferon beta-1b has been shown to reduce viral load of MERS-CoV and improve lung pathology in a nonhuman primate model of common marmoset [42] . Lopinavir/ritonavir and interferon-β1b alone or in combination are being evaluated in clinical trials.

There is a long history of using convalescent plasma as treatment for infectious diseases, including severe viral lower respiratory tract infections [43] . Individuals who have recovered from SARS-CoV-2 infection may generate neutralizing antibodies [44, 45] that could have application to prevention of infection in certain settings, such as individuals with underlying conditions predisposing to severe disease and those with high-risk exposure. Monoclonal antibodies against other respiratory viruses have been shown to be protective against hospitalization in specific high-risk populations [46, 47] and animal models have suggested utility in prophylaxis against SARS coronavirus infection [48] . There are some risks associated with the use of convalescent plasma like transfusion-related acute lung injury or a theoretical risk of antibody-dependent enhancement of infection (ADE). ADE can occur in several viral diseases and involves an enhancement of disease in the presence of certain antibodies [49] . A trial from patients recovered from SARS-CoV-2 infection for use as prophylaxis in adults with a high -risk exposure is expected to begin recruiting shortly [50] .

There are only in vitro data available on the activity of ribavirin on SARS-CoV-2 currently. The EC50 (half maximal effective concentrations) was significantly higher than for chloroquine and remdesivir, so it appears less potent in vitro compared to these agents [51] . There are limited clinical studies in SARS-CoV-1 and MERS-CoV infections. In a systematic review of ribavirin treatment in patients infected with SARS-CoV-1, 26 studies were classified as inconclusive, and four showed possible harm [30] . In a retrospective observational study in patients with MERS-CoV infection, the combination of ribavirin and interferon, compared to no antiviral treatment, was not associated with improvement in the 90-day mortality or more rapid MERS-CoV RNA clearance [52] .

M a n u s c r i p t Oseltamivir Oseltamivir is a neuraminidase inhibitor used for prophylaxis and treatment of influenza. Given its specificity for an enzyme not found on coronaviruses, it is unclear what the mechanism of action would be against COVID-19. However, this has been used in combinations of antiviral therapy in Wuhan [53] and continues to be explored as a therapeutic option as part of combination regimens. Two trials evaluating combination regimens are underway in Wuhan [54, 55] as well as a trial in Thailand proposing different combinations [56] . None of the trials or case reports have examined oseltamivir as monotherapy.

Intravenous immunoglobulin (IVIg) has been used as an adjuvant to treat a variety of pathogens either as a pooled product or in a concentrated more pathogen focused (hyperimmune) form. As the community from which a given batch of IVIg is derived from includes increasing numbers of individuals who have recovered from SARS-CoV-2, the possibility of protective antibodies being present in the pooled product is increased. However, the potential utility of IVIg for the treatment of SARS-CoV-2 is unknown at this time. Its use has been reported in a few patients with COVID-19 [57] , but studies are needed to determine if there may be a role for IVIg in the treatment of SARS-CoV-2.

Remdesivir (GS-5734) is a broad-spectrum antiviral nucleotide prodrug with potent in vitro activity against a range of RNA viruses including Ebola virus, Marburg, MERS-CoV, SARS-CoV, respiratory syncytial virus, Nipah virus, and Hendra virus [58] [59] [60] . The mechanism of action of remdesivir is premature termination of viral RNA transcription [60] . Its use improved disease outcomes and reduced viral loads in SARS-CoV-infected mice [59] . The efficacy of prophylactic and therapeutic remdesivir was tested in a rhesus macaque model of MERS-CoV infection [61] . Prophylactic remdesivir treatment initiated 24 hours prior to inoculation completely prevented MERS-CoV-induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions [61] . Therapeutic remdesivir treatment initiated 12 hours postinoculation reduced clinical signs, virus replication in the lungs, and decreased the presence and severity of lung lesions. A recent case series of 53 patients with severe COVID-19 pneumonia who received remdesivir under a compassionate-use protocol reported clinical improvement in 68% after a median follow-up of 18 days, with 13% mortality and a generally acceptable toxicity profile [62] . However, there was no comparison group of similar patients who received standard care at the participating institutions. Because RCTs for remdesivir have not been completed, formalized recommendations will be made once the entire body of evidence for remdesivir is available.

M a n u s c r i p t Should NSAIDS be stopped in patients infected with COVID-19?

The role of NSAIDs in the management of SARS-CoV2 has been discussed widely. Recent anecdotal reports and subsequent warnings from health officials have suggested against the use of NSAIDs in the care of patients with COVID-19; however, neither FDA, EMA, or WHO have identified evidence linking NSAIDS to COVID-related clinical deterioration. Human coronaviruses, including SARS CoV-2, use ACE2 to bind to human targets and gain entry into target cells [63] . It has been theorized that NSAIDs, due to upregulation in ACE2 in human target cells, may lead to a more severe course of COVID-19 in those taking NSAIDs. While no causal evidence of adverse outcomes with NSAIDs in the management of COVID-19 have been published, there are well known risks of nonsteroidal anti-inflammatory agents including cardiovascular, gastrointestinal and renal adverse events [64, 65] .

In the setting of bacterial pneumonia, NSAIDs may impair recruitment of polymorphonuclear cells, resulting in a delayed inflammatory response and resolution of infection, however a causal relationship has not been established [66, 67] . RCTs are needed to better understand the safety of NSAIDS in the management of patients with COVID-19. One RCT is currently underway to evaluate the role of naproxen in those critically ill with COVID-19 [68] .

Should ACE and ARB's for hypertension be stopped in patients infected with COVID19?

Angiotensin converting enzyme 2 (ACE2) is the receptor for SARS CoV-2 on human cells. Because angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may increase ACE2 expression, the possibility has been raised that these drugs may increase the likelihood of acquiring SARS-CoV-2 or may exacerbate the course of COVID-19. To date, however, there are no clinical data to support this hypothetical concern. For this reason, the American Heart Association, the Heart Failure Society of America and the American College of Cardiology all recommend that ACE inhibitors or ARBs be continued in people who have an indication for these medications [69] .

During epidemics like the current COVID-19 pandemic, when there are no clinically proven treatments, the tendency is to use drugs based on in vitro antiviral activity, or on anti-inflammatory effects or based on limited observational studies. It is commendable that observational studies are done during an epidemic, but often they do not have concurrent controls, have a significant risk of bias, and use surrogate outcomes like viral clearance rather than patient-important outcomes. Medications that were thought to be effective M a n u s c r i p t based on in vitro studies and observational studies for other diseases were later proven to be ineffective in clinical trials [70] .

Due to the understandable urgency in producing, synthesizing and disseminating data during the current pandemic, there has been a noticeable increase in fast track publication of studies. In addition to wellestablished concerns that may decrease our certainty in the available evidence, there may be additional issues that will ultimately influence the trustworthiness of that evidence, including: 1) Circumvention of usual research steps (delay of IRB approval [71] , inclusion of same patients in several studies); 2) Limited peer-review process (the usual due diligence from editors and reviewers is side-stepped, potentially leading to unnoticed errors in data and calculations, incomplete reporting of methods and results, as well as underestimation of study limitations); 3) Increased potential for publication bias (in the interest of showing promising data and in the race to achieve recognition, there may be added inclination to publish positive results and disregard negative ones). The extent and impact of these considerations remain currently uncertain but were acknowledged in the development of this guideline.

Despite these limitations, the recommendations were based on evidence from the best available clinical studies with patient-important endpoints. The panel determined that when an explicit trade-off between the highly uncertain benefits (e.g., the panel was unable to confirm that HCQ increases viral cure or reduces mortality) and the known putative harms (QT prolongation and drug-drug interactions) were considered, a net positive benefit was not reached and could possibly be negative (risk of excess harm). The safety of drugs used for the treatment of COVID-19, especially in patients with cardiovascular disease, immunosuppressive conditions, or those who are critically ill with multi-organ failure has also not been studied. Drugs like azithromycin and hydroxychloroquine can cause QT prolongation and potentially lifethreatening arrhythmias. Steroids and IL-6 inhibitors can be immunosuppressive and potentially increase risk of secondary infections. Steroids may produce long term side effect such as osteonecrosis [72] . Given that the panel could not make a determination whether the benefits outweigh harms for these treatments it would be ethical and prudent to enroll patients with COVID-19 in clinical trials, rather than use clinically unproven therapies [73] . There are multiple ongoing trials, some with adaptive designs, which potentially can quickly answer pressing questions on efficacy and safety of drugs in the treatment of patients with COVID-19.

We acknowledge that enrolling patients in RCTs might not be feasible for many frontline providers due to limited access and infrastructure. Should lack of access to clinical trials exist, we encourage setting up local or collaborative registries to systematically evaluate the efficacy and safety of drugs to contribute to the knowledge base. Without such evaluations we often attribute success to drugs and failure to disease (COVID-19) [70] . During such a pandemic, barriers to conducting studies and enrolling patients in trials for already overburdened front line providers should be minimized while ensuring the rights and safety of patients [74] .

For clinical trials and observational studies, it is critical to determine a priori standardized & practical definitions of patient populations, clinical syndromes, disease severity and outcomes. Observational and non-experimental studies can sometimes answer questions not addressed by trials, but there is still a need for standardized definitions. For clinical syndromes clearly distinguishing between asymptomatic carrier state, upper respiratory tract infection and lower respiratory tract infection is important. Illness severity should be reasonably defined using readily available clinical criteria of end organ failure, like the degree of M a n u s c r i p t respiratory failure using Sa02 or Fi02:Pa02 ratios for lower respiratory tract infection, as opposed to location-based severity determinations such as ICU admission, which can lead to bias based on resource limitations (i.e., bed availability) or regional/institutional practice patterns [75] . For outcomes of prophylaxis trials, the primary endpoint should be prevention of infection and for therapeutic trials patient centered outcomes like reduction of mortality (both short term and long term) [76] . Trials should also study treatments in high risk populations or special populations like immunosuppressed patients, people with HIV, patients with cardiovascular comorbidities and pregnant women. The panel expressed the overarching goal that patients be recruited into ongoing trials, which would provide much needed evidence on the efficacy and safety of various therapies for COVID-19.

This is a living guideline that will be frequently updated as new data emerges. Updates and changes to the guideline will be posted to the IDSA website.

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